Overall-ProjectSummary ObesityisapproachingepidemicproportionsasanutritionalandpathologicaldisorderintheU.S.andisclosely associated with important syndromes including type 2 diabetes, insulin resistance, hepatic steatosis, dyslipidemias, hypertension, coronary heart disease, osteoarthritis and cancer. Obesity rates in the U.S. have continued to worsen whereby nearly 70% of the adult population is overweight and the yearly medical cost of treatment for obesity-related disease is estimated at $190 billion, currently 6X the annual NIH budget. Consequently, obesity is anticipated to overtake smoking as the most preventable cause of adult mortality. Therefore,publichealthinitiativesfocusedonidentifyingtherapeuticoptionstocombatthedetrimentaleffectsof obesity-relateddiseaserelyonanimprovedunderstandingofhowalterationsinmetabolictissuecrosstalkalters metabolism to favor energy accretion and deposition. Our highly synergistic and integrated Program Project teamhasidentifiedpreviouslyunappreciatedmolecularmechanismsthathighlightthecoordinatedactionsofthe hypothalamus(brain),liverandwhiteadiposetissuesasgatekeepersofmetabolicenergybalancethatbecome dysregulatedbyovernutrition.ByfocusingonthemetabolicactionsoftheSteroidReceptorCoactivator(SRC) family as amplifiers of nuclear hormone receptor (NR)/transcription factor (TF) function in this triad of energy- responsive tissues, we have exposed transcriptional reprogramming as a key molecular determinant in the disruption of normal energy homeostasis arising from chronic exposure to caloric excess. Such a complex metabolicregulatoryaxis,whichinvolvestheinterplayofmultipletissuesystems(i.e.brain,liver,adipose),and underlyingtranscriptionalmachinery(NR/SRCs)thatmaintaintheirhomeostaticbalance,canonlybeadequately studiedbyamultidisciplinaryresearchteamwithunique,yetsynergistic,expertise.Leveragingthecollaborative frameworkoftheNIDDKP01ProgramProject,wehaveassembledsuchateamofscientistswhoarededicated totheoverallobjectiveofunderstandingthe?mechanisms?forthedownstreamtissue-specificmetabolicfunctions ofNR/SRCactionthatgovernwholebodyenergybalance.